Hypertrophic scars (keloid) are abnormal proliferation of scar tissue resulting from burns, operative wounds and skin defects after injuries. However, the total number of patients is anticipated to be enormous, and statistics thereof are not available. Although hypertrophic scars resulting from post-operative wounds are of interest to surgery in general, there would be considerable cases wherein hypertrophic scars are left as they are because no effective treatment is available. Therapeutic methods thereof include internal use of tranilast, compression therapy with a sponge, local injection of steroids, and operative treatments such as Z-plasty and dermoplasty. Since therapeutic effects of tranilast and steroids are very mild, only operative treatments may serve as therapies for severe hypertrophic scars. No ointment or injectable preparation suitable for topical administration has been known.
Unlike the above-mentioned hypertrophic scars, keloid (true keloid) is a disease of an unknown cause and is generally said to be influenced by individual's constitutional predispositions. In particular, it is abnormal proliferation of collagen fibers often found in regions such as sternal and shoulder regions, and it develops from both in the presence and absence of a previous injury or an operative wound. Although it is unknown whether the incidence thereof is increasing or not, the number of patients who develop keloid is said to be very large. Therapeutic methods thereof include internal use of tranilast, compression therapy with a sponge, operative treatments, radiation therapies, and the like. However, all these methods have high tendencies of recurrence, and none of them are crucial. No ointment or injectable preparation for this disease is still unknown.
Hypertrophic scars and keloid (sometimes, both are collectively called “keloid”) are progressively enlarging scars due to excessive formation of collagen in the dermis and tumor-like swellings. Hypertrophic scars are those developed in the region confined to a primary lesion. Although the cause and pathogenesis of these scars are unknown, accumulation of collagen fibers, complex tangles of collagen fibers, and an increase in the ratio of types III and I collagen (types III/I) have been reported in these scars.
The incidence of rheumatoid arthritis increases with age. Then, the number of cases developing rheumatoid arthritis will increase as the average life span is increased. Since about 0.5% of a population is assumed to be suffering from this disease, about 30 million people out of the world population of 5.9 billion (UN's Demographic Yearbook, 1998) are suspected to be suffering from rheumatoid arthritis. Since the population of Japan is 120 million, there may exist about 0.6 million of patients with rheumatoid arthritis. When atypical types of rheumatoid arthritis are also included, 1 to 1.5% of the population is considered to be suffering from arthrorheumatic diseases, namely there should be about 2 million patients with arthrorheumatic diseases. This number tends to increase year by year due to prolongation of longevity.
Therapeutic methods of rheumatoid arthritis mainly include surgery and medication. As medication, for example, non-steroidal anti-inflammatory drugs, disease modifying anti-rheumatic drugs and steroidal drugs are used. The treatments often start with non-steroidal anti-inflammatory drugs. These drugs can suppress the inflammation, and rapidly relieve the pain, but they cannot prevent the progression of the disease or destruction and deformity of joints. Disease modifying anti-rheumatic drugs can palliate rheumatic disorder by correcting the immune abnormality. There are nine disease modifying anti-rheumatic drugs, which are slow-acting drugs without an analgesic effect and do not respond constantly. Thus, they are not effective for all of the patients. Steroidal drugs have an effect to reduce the symptoms of the inflammation. However, their effect, particularly analgesic effect, is so marked that it is difficult to stop the use of the drug, leading to poor prognosis with short survival due to side-effects of the steroids. Further, these medication are not cause-related therapeutics for rheumatoid arthritis, but they are symptomatic treatment at present.
Rheumatoid arthritis is a chronic arthritic disease characterized by villous proliferation and hypertrophy of synovial membrane, in which, strong infiltration of lymphocytes, monocytes and macrophages with proliferating capillaries are detectable. Further, inflammatory lesions and necrosis are associated in the capillary endothelial cells. These infiltrating cells produce and secrete IL-1, resulting in deterioration and progression of the conditions. Although the causes seen in the lesions are unknown, it is considered that the conditions can be improved if the collagen production associated with the synovial proliferation that is the essential histopathological features is inhibited, and further, IL-1 secreting cells are killed. These treatments are also expected to be effective for diseases with similar joint conditions such as rheumatoid diseases, arthritis with collagenosis, and chronic arthritic diseases such as tendovaginitis, etc.
Erythropoietin (EPO) is involved in proliferation and differentiation of blood cells. Unlike other cytokines, it is not produced in the blood cells, but is produced in kidneys or livers and secreted into blood. Erythropoietin is considered to act on burst forming unit-erythroid (BFU-E) and colony forming unit-erythroid (CFU-E) among erythroid progenitor cells, stimulates them to proliferate and differentiates into erythrocytes (Krantz S. B., Blood, vol. 77, pp. 419-434 (1991)). It is said that, when erythropoietin binds to its cognate receptor on the cell membrane of the progenitor cells, the signal is transduced into the cell nucleus and leads to erythrocyte differentiation, i.e., intracellular accumulation of globin mRNA, hemoglobin production and erythrocyte differentiation (D'Andrea A. D. et al, Cell, vol. 57, pp. 277-285 (1989)). However, the detailed mechanism thereof has not yet been elucidated, and there are many problems to be solved in the future.
In addition to kidney and liver, embryos of the early post-implantation stage (Yasuda Y. et al., Develop. Growth Differ., vol. 35, pp.711-722 (1993)), and brains of humans, monkeys and mice (Marti H. H. et al., Eur. J. Neu. Sci, vol. 8, pp. 666-676 (1996)) have been known to be expression sites of an erythropoietin gene. The present inventors have found that an erythropoietin receptor gene is expressed in mouse decidua in addition to erythroblasts (Yasuda Y. et al., Develop. Growth Differ., vol. 35, pp.711-722 (1993)). Functions of erythropoietin and erythropoietin receptor genes expressed in non-hematopoietic sites are still unknown at present.
Erythropoietin is produced by gene recombinant technique and beneficially used in the treatment of anemia, particularly in anemic patients undergoing kidney dialysis, and in patients in preparation for autologous transfusion during surgery. Erythropoietin receptors are expected to be used as agonists for anemia and antagonists for polycythemia (WO90/08822), and there is described that erythropoietin receptors can be used in the treatment of hypererythropoietinosis and hypererythropoietinemia. Further, there is described that a material which can bind to an erythropoietin receptor at a specific domain may be used in the treatment of chronic rheumatoid arthritis (WO00/66632).
However, while erythropoietin antagonists (erythropoietin-binding substances) such as anti-erythropoietin antibody and erythropoietin receptor protein, are known to have a therapeutic effect on proliferative diseases of the organs such as tumor (JP 10-101574 A), none of their prophylactic and/or therapeutic effects on excessive (unusual) collagenous proliferation such as hypertrophic scars or keloid, and chronic arthritic diseases such as rheumatoid arthritis has been known so far.